An Eμ-BCL-2 transgene facilitates leukaemogenesis by ionizing radiation

Abstract

Clonogenic murine B cell precursors are normally ultra-sensitive to apoptosis following genotoxic exposure in vitro but can be protected by expression of an Eμ-BCL-2 transgene. Such exposures are likely to be mutagenic. This in turn suggests that a level of in vivo genotoxic exposure that usually has minimal pathological consequences might become leukaemogenic when damaged cells fail to abort by apoptosis. If this were to be the case, then the cell type that becomes leukaemic and the chromosomal/molecular changes that occur would also be of considerable interest. We tested this possibility by exposing Eμ-BCL-2 and wild-type mice of differing ages to a single dose of X-irradiation of 1 – 4 Gy. Young (∼4 – 6 weeks) transgenic mice developed leukaemia at a high rate following exposure to 2 Gy but adult mice (4 – 6 months) did not. Exposure to 4 Gy produced leukaemia in both young and adult transgenic mice but at a higher frequency in the former. Leukaemic cell populations showed clonal rearrangements of the IGH gene but in most cases analysed had immunophenotypic features of an early B lympho-myeloid progenitor population which has not previously been recorded in radiation leukaemogenesis. Molecular cytogenetic analysis of leukaemic cells by banded karyotype and FISH revealed a consistent double abnormality: trisomy 15 plus an interstitial deletion of chromosome 4 that was confirmed by LOH analysis.